Patients with chronic kidney disease (CKD) are at 10-fold higher risk of cardiovascular disease incidence and mortality than an age control group, and have recently increased in a geometric progression (Schieppati A, Remuzzi G: Chronic renal diseases as a public health problem: epidemiology, social, and economic implications. Kidney Int Suppl. 98:S7-S10, 2005(1)).
CKD is characterized by epithelial-to-mesenchymal transition (EMT) and accumulation of extracellular matrix (ECM) proteins, and exhibits various pathological traits including basement membrane thickening of glomerular capillaries, glomerular mesangial expansion, renal tubular interstitial fibrosis, glomerular hypertrophy and nephromegaly, and proteinuria. Transforming growth factor-β1 (TGF-β1), a factor implicated in renal fibrosis, serves as a final mediator in the production of extracellular matrix proteins in response to various stimuli and thus is regarded as a fibrosis indicator (Qian Y, Feldman E, Pennathur S, Kretzler M, Brosius F C 3rd: From fibrosis to sclerosis: mechanisms of glomerulosclerosis in diabetic nephropathy. Diabetes. 57: 1439-45, 2008).
Diabetic kidney disease (DKD), which is a kind of CKD, is the most common cause of end-stage renal disease (ESRD) (U.S. Renal Data System, USRDS 2011 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., 2011).
Treatment modalities, known thus far, for restraining the progression of CKD including DKD to end-stage renal disease include the throughgoing control of blood pressure and the use of renin-angiotensin system (RAS) blocker, but there is still a need for a therapeutic agent that guarantees perfect nephroprotective effect (Zhang M Z, Wang S, Yang S, Yang H, Fan X, Takahashi T, Harris R C: The Role of Blood Pressure and the Renin-Angiotensin System in Development of Diabetic Nephropathy (DN) in eNOS−/− db/db Mice. Am J Physiol Renal Physiol. Epub ahead of print, 2011).